9-131522077-C-T

Variant names:

• chr9-131522077-C-T
• rs12115566
• NM_001077365.2:c.1856C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001077365.2(POMT1):​c.1856C>T​(p.Ala619Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00491 in 1,614,056 control chromosomes in the GnomAD database, including 107 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A619A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.015 (59 hom., cov: 33)
  • Exomes 𝑓: 0.0038 (48 hom.)
• Consequence: POMT1 NM_001077365.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.797
• Publications: 11 publications found

Genes affected

POMT1 (HGNC:9202): (protein O-mannosyltransferase 1) The protein encoded by this gene is an O-mannosyltransferase that requires interaction with the product of the POMT2 gene for enzymatic function. The encoded protein is found in the membrane of the endoplasmic reticulum. Defects in this gene are a cause of Walker-Warburg syndrome (WWS) and limb-girdle muscular dystrophy type 2K (LGMD2K). Several transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Oct 2008]

POMT1 Gene-Disease associations (from GenCC):

• muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, Genomics England PanelApp, G2P
• myopathy caused by variation in POMT1

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• autosomal recessive limb-girdle muscular dystrophy type 2K

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital muscular dystrophy with cerebellar involvement

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital muscular dystrophy with intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital muscular dystrophy without intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• muscle-eye-brain disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• muscular dystrophy-dystroglycanopathy, type A

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000230289 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031572282).
• BP6: Variant 9-131522077-C-T is Benign according to our data. Variant chr9-131522077-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130011.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0154 (2352/152268) while in subpopulation AFR AF = 0.0477 (1983/41540). AF 95% confidence interval is 0.046. There are 59 homozygotes in GnomAd4. There are 1138 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 59 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001077365.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POMT1	NM_001077365.2	MANE Select	c.1856C>T	p.Ala619Val	missense	Exon 19 of 20	NP_001070833.1	A0A140VKE0
	POMT1	NM_001353193.2		c.1922C>T	p.Ala641Val	missense	Exon 19 of 20	NP_001340122.2	Q9Y6A1-1
	POMT1	NM_007171.4		c.1922C>T	p.Ala641Val	missense	Exon 19 of 20	NP_009102.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POMT1	ENST00000402686.8	TSL:1 MANE Select	c.1856C>T	p.Ala619Val	missense	Exon 19 of 20	ENSP00000385797.4	Q9Y6A1-2
	POMT1	ENST00000372228.9	TSL:1	c.1922C>T	p.Ala641Val	missense	Exon 19 of 20	ENSP00000361302.3	Q9Y6A1-1
	POMT1	ENST00000423007.6	TSL:1	c.1913C>T	p.Ala638Val	missense	Exon 18 of 19	ENSP00000404119.2	A0A1V1FTP4

Frequencies

GnomAD3 genomes AF: 0.0154 AC: 2343 AN: 152150 Hom.: 58 Cov.: 33

Gnomad AFR AF: 0.0476

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00530

Gnomad ASJ AF: 0.00606

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00828

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00273

Gnomad OTH AF: 0.0158

GnomAD2 exomes AF: 0.00665 AC: 1671 AN: 251270 AF XY: 0.00628

Gnomad AFR exome AF: 0.0489

Gnomad AMR exome AF: 0.00477

Gnomad ASJ exome AF: 0.00447

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000603

Gnomad NFE exome AF: 0.00335

Gnomad OTH exome AF: 0.00505

GnomAD4 exome AF: 0.00381 AC: 5571 AN: 1461788 Hom.: 48 Cov.: 31 AF XY: 0.00393 AC XY: 2861 AN XY: 727194

African (AFR) AF: 0.0476 AC: 1592 AN: 33480

American (AMR) AF: 0.00501 AC: 224 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00440 AC: 115 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00813 AC: 701 AN: 86258

European-Finnish (FIN) AF: 0.000900 AC: 48 AN: 53322

Middle Eastern (MID) AF: 0.0121 AC: 70 AN: 5768

European-Non Finnish (NFE) AF: 0.00218 AC: 2420 AN: 1112008

Other (OTH) AF: 0.00662 AC: 400 AN: 60392

GnomAD4 genome AF: 0.0154 AC: 2352 AN: 152268 Hom.: 59 Cov.: 33 AF XY: 0.0153 AC XY: 1138 AN XY: 74472

African (AFR) AF: 0.0477 AC: 1983 AN: 41540

American (AMR) AF: 0.00529 AC: 81 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00606 AC: 21 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00787 AC: 38 AN: 4826

European-Finnish (FIN) AF: 0.000753 AC: 8 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00273 AC: 186 AN: 68020

Other (OTH) AF: 0.0157 AC: 33 AN: 2108

Alfa AF: 0.00753 Hom.: 34

Bravo AF: 0.0168

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.0415 AC: 183

ESP6500EA AF: 0.00244 AC: 21

ExAC AF: 0.00757 AC: 919

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.00431

EpiControl AF: 0.00379

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2K (1)
-	-	1	Walker-Warburg congenital muscular dystrophy;C1836373:Autosomal recessive limb-girdle muscular dystrophy type 2K;C5436962:Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	6.2
DANN	Benign	0.93
DEOGEN2	Uncertain	0.64	D
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.39	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.80
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.18
Sift	Benign	0.32	T
Sift4G	Benign	0.29	T
Polyphen		0.012	B
Vest4		0.19
MVP		0.82
MPC		0.25
ClinPred		0.0026	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.022
gMVP		0.22
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs12115566; hg19: chr9-134397464;